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We read with great interest the paper of Hanajimaet al 1 reporting that intracortical inhibition of the motor cortex is normal in patients with chorea of various origins. At variance with these results we previously found2 a reduced intracortical inhibition in a group of patients with genetically confirmed Huntington's disease. Hanajimaet al suggest that the discrepancies between the two studies might be due to differences in patient selection as they included patients with early stage Huntington's disease to “study the pathophysiology of chorea unaffected by other disorders movement.” They postulated that our cases, because of the reported correlation with a dyskinesia rating scale, had a more advanced stage of the disease possibly with coexisting dystonia or rigidity. These assertions deserve some comments.
The mean disease duration of our nine patients with Huntington's disease was 6.2 (4.1) years which is actually shorter than the duration of the six patients reported by Hanajima et al (8.3 (5.9) years). Most of our patients could be considered in an early stage of the disease, according to the Unified Huntington's disease rating scale, and none presented dystonia, rigidity, or any other additional movement disorder. In this regard, however, it should be pointed out that bradykinesia is often associated with chorea in patients with Huntington's disease3 and may even precede the appearance of choreic dyskinesias.4Chorea itself is often reduced in the more advanced Huntington's disease stages.4 It is unlikely, therefore, that any neurophysiological approach can test purely chorea even in the early Huntington's disease stages. In addition, different mechanisms are involved in Huntington's disease and other choreas as suggested by the lack of impairment of somatosensory evoked responses and long latency stretch reflexes in the second.5
We were not really surprised at the results of Hanajimaet al as we do share their opinion that patients with Huntington's disease may be characterised by large individual differences in the involvement of motor cortical areas. Actually, three patients in our study showed an amount of intracortical inhibition within the confidence limits of the control population. We also think that the impairment of intracortical inhibition is likely to develop during the disease progression as we did not find any change in four patients, two of them already reported,2 with positive DNA testing but completely asymptomatic.
The discrepancies between the two studies are more likely to be explained, at least in part, by some methodological differences. For instance, the amplitude of the control response was larger in our set (approximately 1.0 mV compared with 0.3 mV in the study of Hanajimaet al). This may induce a different sensitivity of the test, and the amount of intracortical inhibition in our normal controls is greater (see also6) than in the study of Hanajima et al.
When interpreting the results of studies with paired transcranial magnetic stimulation pathophysiologically it should be kept in mind that similar changes of intracortical inhibition have been shown in patients with various movement disorders (focal dystonia, myoclonus, parkinsonism, restless legs syndrome, Tourette's disorder), but also in different diseases such as amyotrophic lateral sclerosis.7 We think, therefore, that the impairment of intracortical inhibition cannot be regarded as the marker of a specific pathophysiological mechanism, but is likely to reflect a non-specific imbalance of inhibitory and facilitatory circuits within the motor cortex.
The authors reply:
We are very grateful for the response of Abbruzzeseet al to our paper. We completely agree with their opinions.
The discrepancy between the two studies1-1 1-2 may not be mainly due to the different stage of the disease between the two groups of patients. Although the duration of the disease is one factor to judge the disease stage, the severity of the disease (stage of the disease) is also positively correlated with CAG repeat number.
We may have to take CAG repeat number into consideration in comparisons. Unfortunately, however, we have no way to do such comparisons between these two studies. We could say, at least, that the intracortical inhibition was normal even at the same stage of the disease as that of the patients of Abbruzzese et al, if studied with our method.
We also consider that methodological differences are very important in paired magnetic stimulation. The results strongly depend on the intensities of both a conditioning and a test stimulus. Especially, the intensity of the conditioning stimulus is critical. We have no difficulty in showing normal inhibition, but have much difficulty in showing reduced or absent inhibition because of such marked dependence of the results on the intensities of stimuli. Therefore, we used several intensities of the conditioning stimulus before we confirmed inhibition in studies of patients.1-3 We used an intensity of 5% less than the active threshold as a conditioning stimulus in our study of chorea.1-2 We did not need to change the intensity of the conditioning stimulus because we always obtained a normal inhibition with this intensity. We consider that this is very important. If using a suprathreshold (active threshold) conditioning stimulus, a facilitatory effect must often superimpose on the intracortical inhibition. This makes the interpretation difficult. Was the intensity of 80% of the resting threshold always below the active threshold in their patients? In our experience, 80% of the resting threshold was sometimes above the active threshold. These factors must be considered in interpreting the results of paired magnetic stimulation.
Such a methodological problem is inherent in human studies because we have no direct way of detecting the threshold of the motor cortex. Our two results must be true. We may have two completely different interpretations of these results. (1) The intracortical inhibition is normal in Huntington's disease. Abbruzzese et al showed the reduced inhibition because they used a high intensity conditioning stimulus with which the degree of the intracotical inhibition is often decreased even in normal subjects. The 80% of the threshold for relaxed muscles must correspond to different values relative to the threshold for active muscles in patients from that in normal subjects. (2) The intracortical inhibition is disturbed in Huntington's disease. This slight abnormality could be detected with their method but not with ours because their method has better sensitivity in detecting an abnormality than ours. Whichever is true, the intracortical inhibition must be normal or slightly disturbed in Huntington's disease.